For centuries, green tea has been used as a therapy for many different diseases ranging from cancer to inflammatory disorders. Over the last few years, investigators have begun to elucidate several mechanisms of action of the primary active ingredient known as EGCG, and controlled trials have been initiated for the treatment of various cancers and other studies have been proposed for inflammatory diseases. However, one of the most important factors in the ultimate clinical success of a therapeutic compound is choosing the right disease to target. Many common diseases have complex pathways with multifactorial pathogenesis making it difficult to demonstrate adequate clinical efficacy. Therefore, we have chosen to study a rare inherited disease known as cryopyrin associated periodic syndrome (CAPS) by identifying the causative gene and uncovering the inflammatory pathways involved in this disease, which has resulted in novel and effective targeted therapies. Further studies have shown similar pathogenesis in the related inflammatory disease gout and this has been confirmed by effective treatment with the same targeted therapies used in CAPS. We propose to take the same developmental approach in aim 1 of our study of green tea by investigating the role of EGCG in CAPS mediated inflammation and cell death using cells from human CAPS patients and knockin mutant mice designed to have the same mutations observed in human patients. We hypothesize that green tea will have multiple mechanisms of action and therefore propose to compare the effects of EGCG to other compounds with known mechanisms at various points in the inflammatory pathways of CAPS. In aim 2, we will study the effects of EGCG on ex vivo and in vivo models of inflammation mediated by monosodium urate (MSU), the cause of the common disease gout. Although therapies are now available for CAPS and gout, treatments are either extremely expensive (IL-1 targeted therapy in CAPS) or poorly tolerated by many patients due to side effects (gout). Therefore, development of EGCG as a novel therapy with the potential advantage of multiple mechanisms of action and few side effects would meet an unmet clinical need. PUBLIC HEALTH RELEVANCE: Green tea is known for its potential anti-inflammatory and anti cancer therapeutic properties;however, the mechanisms responsible for these actions are not well understood. This proposal will focus on the effects of green tea on two inflammatory disease models including the rare cryopyrin associated periodic syndrome and the common disease gout. Results of this study will be used to design clinical trials of green tea in patients with these diseases.